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Metal-free carbonitration of alkenes using K2S2O8† Cite this: Chem. Commun., 2013, 49, 11701
Ya-Min Li,a Xiao-Hong Wei,a Xi-An Lia and Shang-Dong Yang*ab
Received 24th September 2013, Accepted 15th October 2013 DOI: 10.1039/c3cc47287f www.rsc.org/chemcomm
A novel metal-free oxidative carbonitration of alkenes by a nitration and C–H functionalization cascade process has been developed. This methodology provides an efficient way to construct valuable nitrocontaining oxindoles.
Nitro compounds are widely used in organic synthesis, the chemical industry, and pharmaceuticals. These important synthetic precursors can be easily transformed into various functional groups such as amines and ketones.1 In general, electrophilic aromatic substitution that involves a nitrating agent has been the predominant synthetic approach for the preparation of nitroarenes.2 Recently, transition-metal-catalyzed synthesis of nitroaromatics from aryl chlorides, triflates, and nonaflates has also been developed.3 For aliphatic nitro compounds, however, nucleophilic substitution reaction of an alkyl halide with the nitrite anion (NO2 )4 is the common method. Moreover, oxidation of amines and oximes also affords corresponding nitro compounds.5 These methods require large amounts of base or a specifically functionalized precursor, which significantly limits their application scope. Although direct addition of nitrogen dioxide to a C–C multiple bond provides the simplest pathway of affording aliphatic nitro compounds, the difficulty in handling NO2 gas and its toxicity dramatically decrease the overall reaction efficiency.1a On the other hand, C–C bond-formation reactions involving nitroalkanes also promise alternative methods, including the Henry reaction,6 conjugate additions,7 alkylation of nitroalkanes with alkyl halides8 and Pd-catalyzed allylation,9 and arylation.10 Unfortunately, few substrates are compatible with nitro compounds, which further restricts availability. Therefore, the development of a more concise and efficient nitrating method for the preparation of aliphatic nitro compounds is highly desirable and presents a considerable challenge to research. Recently, transformations that result in the difunctionalization of alkenes have a
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. China. E-mail: [email protected]; Fax: +86-931-8912859; Tel: +86-931-8912859 b State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Lanzhou 730000, P. R. China † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c3cc47287f
This journal is
c
The Royal Society of Chemistry 2013
Scheme 1
Metal-free carbonitration of alkenes.
become an active topic in organic synthesis.11 In particular, transition-metal-catalyzed carbo–heterodifunctionalization of alkenes that leads to cyclization offers a new pathway for the synthesis of various functional oxindoles.12 We envisioned direct installation of the nitro group into alkenes by carbonitration and conducted the necessary cyclization in order to afford the corresponding nitrocontaining oxindoles. After great efforts, we report transition-metal free carbonitration–difunctionalization of arylacrylamides (Scheme 1). Over the past several years, the development of transition-metalfree processes has become a topic of great interest in chemical synthesis.13 Such protocols are very valuable as attractive alternatives and beneficial complements to transition-metal-catalyzed transformations. In particular, the transition-metal-free C–H functionalization has attracted the most attention and achieved significant progress;14 indeed, this of all methods among the metal free processes that involve difunctionalization of alkenes appears particularly fascinating.15 Current reports mainly focus on the oxidative difunctionalization of alkenes; therefore, examples that involve the oxidative carbo–heterocascade cyclization of alkenes are very rare.16 Using the very cheapest NaNO2 as a nitrogen source and K2S2O8 as the oxidant, we first accomplished metal-free oxidative carbonitration of alkenes towards the nitro-containing oxindoles through a radical process. In an initial study, we chose the N-methyl-N-arylacrylamide 1a as the model substrate and NaNO2 as a nitrating source to evaluate different oxidants in CH3CN at 120 1C. To our delight, the carbonitration of alkenes could occur in the presence of 2.0 equiv. of oxidants such as Na2S2O8, (NH4)2S2O8, K2S2O8, and oxone, while the reactivity of K2S2O8 was better than others to afford the desired Chem. Commun., 2013, 49, 11701--11703
11701
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Table 1
ChemComm
Carbonitration of different alkenesa,b
Scheme 2
a
All reactions were carried out in the presence of 0.4 mmol of 1a–1z, NaNO2 (2.0 equiv.), K2S2O8 (2.0 equiv.) in 2 mL of CH3CN at 120 1C. b Isolated yield.
product 2a in 71% yield (see the ESI†). Besides NaNO2, other nitrites could also be used to give good yields of 2a: AgNO2: 66%; KNO2: 70%. The substrate concentration highly affected this transformation. When the substrate concentration was increased to 0.2 M, the yield of 2a improved to 86%. Different solvents were screened, and among them CH3CN exhibited unmatched efficacy for the transformation. Upon optimization of the reaction conditions, we turned our attention to the scope of substrates. As shown in Table 1, an investigation into different N-protection groups showed that the electron-donating groups such as methyl and benzyl are suitable for this reaction (2a–2b). However, replacement of the methyl substituent with a hydrogen atom failed to produce corresponding products. N-Arylacrylamides bearing electron-donating or electron-withdrawing substituents on aniline moieties could be successfully converted into the desired products in moderateto-good yields (2d–2m). Cyclization of a tetrahydroquinoline derivative furnished tricyclic oxindole 2d with moderate yield. Notably, Cl, Br, and I groups were also well tolerated, thereby facilitating possible additional modifications at halogenated positions (2i–2k). Next, we evaluated various alkene substituent groups. A series of a-substituted olefines bearing different functional groups, such as benzyl (2n), acetoxymethyl (2o), phthalimide (2p), and azidoethyl (2q), still provided the desired products in moderate to good yields. It is worth noting that unactivated alkenes can also undergo carbonitration smoothly, generating corresponding products in moderate yields (2r–2x). Finally, the polycyclic aromatic hydrocarbon such as naphthalene was compatible with this reaction and the desired product 2y was obtained in 71% yield. But pyridineacrylamide produced only a trace amount of the product 2z. 11702
Chem. Commun., 2013, 49, 11701--11703
Some reactions on the nitro unit.
Nitro groups feature facile transformation into various functional groups, a versatility that has broadened their importance in the synthesis of complex molecules.1 On the other hand, 3-substituted oxindoles are ubiquitous heterocycles found in a wide range of natural products, pharmaceuticals, and agrochemicals.17 We demonstrate herein the postsynthetic transformations of nitrocontaining oxindoles (Scheme 2). Compound 2a can be further transformed into 1,3-dimethylindolin-2-one (3a) in moderate yield using the oxone–NaOH system. Moreover, KMnO4-oxidized reaction conditions were employed to obtain 3-hydroxyoxindole 3b in good yield from 2a. Finally, compound 2a was also reduced with ammonium formate and Pd/C to give the primary amine 3c. These representative transformations clearly demonstrate that the presented methodology provides an efficient and atom economical access to various valuable 3-substituted oxindoles. To probe the mechanism of the carbonitration process, substrate [D1]-1a was used to determine the intramolecular isotope effect, and a mixture of substrates 1a and [D5]-1a in a 1 : 1 ratio was used to determine the intermolecular isotope effect (see the ESI†). Two secondary kinetic isotope effects were observed (the intramolecular kH/kD = 0.9, intermolecular kH/kD = 0.8). These findings suggested that this transformation reaction might involve a freeradical process similar to mechanisms proposed in previously reports.12e, f,16 In addition, control experiments support the freeradical mechanism in the presence of radical inhibitors. Addition of 2.0 equivalents of TEMPO or 1,1-diphenylethylene would led the carbonitration process remarkably suppressed. Based on the above experiments and previous mechanistic studies,12d–g,16 we propose a tentative pathway of this transformation described in Scheme 3. Initially, potassium peroxydisulphate may decompose to the sulfate radical anion upon heating.18 Then, NaNO2 reacts with the sulfate radical anion to form a nitrogen dioxide radical, followed by addition to the carbon–carbon double bond of amide 1a, thus affording radical intermediate 2A.19 The resulting alkyl radical 2A participates in an intramolecular radical substitution reaction. Addition of a radical to the aromatic ring led to the generation of intermediate 2B, followed by oxidation of 2B into the corresponding carbocation, which loses H+ to produce the oxindole 2a. In summary, we have developed a novel metal-free oxidative carbonitration of alkenes by a nitration and C–H functionalization cascade process using the K2S2O8 as oxidant. This methodology provides the most efficient way to construct nitro-containing oxindoles, which are important synthetic intermediates. Further applications of this new transformation to other substrates and This journal is
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The Royal Society of Chemistry 2013
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12
Scheme 3
Proposed mechanisms for carbonitration of alkenes.
13
the synthesis of more valuable compounds are underway in our group. We are grateful to the NSFC (No. 21272100), Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT: IRT1138) and Research Fund for the Doctoral Program of Higher Education of China (No. 20100211120014) for financial support. We thank S. F. Reichard, MA, for editing the manuscript.
14
Notes and references 1 (a) N. Ono, The Nitro Group in Organic Synthesis, Wiley-VCH, New York, 2001; (b) H. Feuer and A. T. Nielson, Nitro Compounds: Recent Advances in Synthesis and Chemistry, VCH, Weinheim, 1990; (c) A. G. M. Barrett and G. G. Graboski, Chem. Rev., 1986, 86, 751. 2 (a) G. A. Olah, R. Malhotra and S. C. Narang, Nitration: Methods and Mechanisms, VCH, Weinheim, 1989; (b) K. Schofield, Aromatic Nitration, Cambridge University Press, Cambridge, 1980; (c) P. J. Campos, B. Garcı´a and M. A. Rodrı´guez, Tetrahedron Lett., 2000, 41, 979; (d) I. Jovel, S. Prateeptongkum, R. Jackstell, N. Vogl, C. Weckbecker and M. Beller, Adv. Synth. Catal., 2008, 350, 2493; (e) H. Sprecher, ¨ri and R. Marti, Helv. Chim. Acta, 2010, 93, 90; S. Pletscher, M. Mo ( f ) T. Taniguchi, T. Fujii and H. Ishibashi, J. Org. Chem., 2010, 75, 8126. 3 (a) S. Saito and Y. Koizumi, Tetrahedron Lett., 2005, 46, 4715; (b) B. P. Fors and S. L. Buchwald, J. Am. Chem. Soc., 2009, 131, 12898; (c) G. K. S. Prakash and T. Mathew, Angew. Chem., Int. Ed., 2010, 49, 1726. 4 (a) H. J. Schneider and R. Busch, Angew. Chem., Int. Ed. Engl., 1984, 23, 911; (b) D. A. Evans, D. H. B. Ripin, D. Halstead and K. R. Campos, J. Am. Chem. Soc., 1999, 121, 6816. 5 (a) B. Jayachandran, M. Sasidharan, A. Sudalai and T. Ravindranathan, J. Chem. Soc., Chem. Commun., 1995, 1523; (b) J. M. Vega-Perez, J. I. Candela and F. Iglesias-Guerra, J. Org. Chem., 1997, 62, 6608. 6 (a) M. T. El-Sayed, K. Mahmoud and A. Hilgeroth, Curr. Org. Chem., ´s-Lo ´pez, P. Merino, T. Tejero and 2013, 17, 1200; (b) E. Marque P. R. Herrera, Eur. J. Org. Chem., 2009, 2401; (c) C. Palomo, M. Oiarbide and A. Laso, Eur. J. Org. Chem., 2007, 2561. 7 (a) R. Ballini, G. Bosica, D. Fiorini, A. Palmieri and M. Petrini, Chem. Rev., 2005, 105, 933; (b) R. Ballini, L. Barboni, G. Bosica, D. Fiorini and A. Palmieri, Pure Appl. Chem., 2006, 78, 1857. 8 (a) A. R. Katritzky, M. A. Kashmiri, G. Z. De Ville and R. C. Patel, J. Am. Chem. Soc., 1983, 105, 90; (b) P. G. Gildner, A. A. S. Gietter, D. Cui and D. A. Watson, J. Am. Chem. Soc., 2012, 134, 9942. 9 (a) B. M. Trost and J.-P. Surivet, Angew. Chem., Int. Ed., 2000, 39, 3122; (b) K. Maki, M. Kanai and M. Shibasaki, Tetrahedron, 2007, 63, 4250; (c) H. Rieck and G. Helmchen, Angew. Chem., Int. Ed. Engl., 1995, 34, 2687. 10 E. M. Vogl and S. L. Buchwald, J. Org. Chem., 2002, 67, 106. 11 Reviews for the difunctionalization of alkenes: (a) P. A Sibbald, Palladium-catalyzed oxidative difunctionalization of alkenes: New reactivity and new mechanisms, ProQuest, UMI Dissertation Publishing, ˜ iz, in Catalyzed Carbon–Heteroatom 2011; (b) B. Jacques and K. Mun Bond Formation, ed. A. K. Yudin, Wiley, VCH, 2011, p. 119; (c) R. I. McDonald, G. Liu and S. S. Stahl, Chem. Rev., 2011,
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˜iz, Angew. Chem., Int. Ed., 2009, 48, 9412; 111, 2981; (d) K. Mun (e) S. R. Chemler, Org. Biomol. Chem., 2009, 7, 3009; ( f ) K. H. Jensen and M. S. Sigman, Org. Biomol. Chem., 2008, 6, 4083; (g) V. Kotov, C. C. Scarborough and S. S. Stahl, Inorg. Chem., 2007, 46, 1910; (h) G. Li, S. R. S. S. Kotti and C. Timmons, Eur. J. Org. Chem., 2007, 2745. (a) S. Jaegli, J. Dufour, H. Wei, T. Piou, X. Duan, J. Vors, L. Neuville and J. Zhu, Org. Lett., 2010, 12, 4498; (b) T. Wu, X. Mu and G. Liu, Angew. Chem., Int. Ed., 2011, 50, 12578; (c) X. Mu, T. Wu, H. Wang, Y. Guo and G. Liu, J. Am. Chem. Soc., 2012, 134, 878; (d) W.-T. Wei, M.-B. Zhou, J.-H. Fan, W. Liu, R.-J. Song, Y. Liu, M. Hu, P. Xie and J.-H. Li, Angew. Chem., Int. Ed., 2013, 52, 3638; (e) Y.-M. Li, M. Sun, H.-L. Wang, Q.-P. Tian and S.-D. Yang, Angew. Chem., Int. Ed., 2013, 52, 3972; ( f ) X.-H. Wei, Y.-M. Li, A.-X. Zhou, T.-T. Yang and S.-D. Yang, Org. Lett., 2013, 15, 4151; ( g) H. Wang, L.-N. Guo and X.-H. Duan, Adv. Synth. Catal., 2013, 355, 2222. (a) A. Bhunia, S. R. Yetra and A. T. Biju, Chem. Soc. Rev., 2012, 41, 3140; (b) S. Murarka, S. Wertz and A. Studer, Chimia, 2012, 66, 413; (c) V. P. Mehta and B. Punji, RSC Adv., 2013, 3, 11957; (d) A. Beyer, J. Buendia and C. Bolm, Org. Lett., 2012, 14, 3948; (e) D. C. Fabry, M. Stodulski, S. Hoerner and T. Gulder, Chem.–Eur. J., 2012, 18, 10834; ( f ) H. Liu, B. Yin, Z. Gao, Y. Li and H. Jiang, Chem. Commun., 2012, 48, 2033. (a) W. Tu, L. Liu and P. E. Floreancig, Angew. Chem., Int. Ed., 2008, 47, 4184; (b) C.-L. Sun, H. Li, D.-G. Yu, M. Yu, X. Zhou, X.-Y. Lu, K. Huang, S.-F. Zheng, B.-J. Li and Z.-J. Shi, Nat. Chem., 2010, 2, 1044; (c) W. Liu, H. Cao, H. Zhang, H. Zhang, K. H. Chung, C. He, H. Wang, F. Y. Kwong and A. Lei, J. Am. Chem. Soc., 2010, 132, 16737; (d) H. J. Kim, J. Kim, S. H. Cho and S. Chang, J. Am. Chem. Soc., 2011, 133, 16382; (e) T. Froehr, C. P. Sindlinger, U. Kloeckner, P. Finkbeiner and B. J. Nachtsheim, Org. Lett., 2011, 13, 3754; ( f ) T. Truong and O. Daugulis, J. Am. Chem. Soc., 2011, 133, 4243; ( g) S. Ghosh, S. De, B. N. Kakde, S. Bhunia, A. Adhikary and A. Bisai, Org. Lett., 2012, 14, 5864; (h) W. Liu, F. Tian, X. Wang, H. Yu and Y. Bi, Chem. Commun., 2013, 49, 2983; (i) B. Li, X. Qin, J. You, X. Cong and J. Lan, Org. Biomol. Chem., 2013, 11, 1290. (a) H. M. Lovick and F. E. Michael, J. Am. Chem. Soc., 2010, 132, 1249; (b) V. A. Schmidt and E. J. Alexanian, Angew. Chem., Int. Ed., 2010, 49, 4491; (c) P. Pandit, K. S. Gayen, S. Khamarui, N. Chatterjee and D. K. Maiti, Chem. Commun., 2011, 47, 6933; (d) V. A. Schmidt and E. J. Alexanian, J. Am. Chem. Soc., 2011, ¨ben, J. A. Souto, Y. Gonza ´lez, A. Lishchynskyi 133, 11402; (e) C. Ro ˜ iz, Angew. Chem., Int. Ed., 2011, 50, 9478; ( f ) U. Farid and K. Mun and T. Wirth, Angew. Chem., Int. Ed., 2012, 51, 3462; ( g) Q. Lu, J. Zhang, F. Wei, Y. Qi, H. Wang, Z. Liu and A. Lei, Angew. Chem., Int. Ed., 2013, 52, 7156. For the metal-free oxidative difunctionalization of alkenes leading to oxindoles via a radical process, see: (a) T. Wu, H. Zhang and G. Liu, Tetrahedron, 2012, 68, 5229; (b) M.-B. Zhou, R.-J. Song, X.-H. Ouyang, Y. Liu, W.-T. Wei, G.-B. Deng and J.-H. Li, Chem. Sci., 2013, 4, 2690; (c) Y. Meng, L.-N. Guo, H. Wang and X.-H. Duan, Chem. Commun., 2013, 49, 7540; (d) K. Matcha, R. Narayan and A. P. Antonchick, Angew. Chem., Int. Ed., 2013, 52, 7985; (e) X. Li, X. Xu, P. Hu, X. Xiao and C. Zhou, J. Org. Chem., 2013, 78, 7343. For recent reviews and selected papers on synthesis of oxindoles, see: (a) C. V. Galliford and K. A. Scheidt, Angew. Chem., Int. Ed., 2007, 46, 8748; (b) B. Trost and M. K. Brennan, Synthesis, 2009, 3003; (c) A. Millemaggi and R. J. K. Taylor, Eur. J. Org. Chem., 2010, 4527; (d) F. Zhou, Y.-L. Liu and J. Zhou, Adv. Synth. Catal., 2010, 352, 1381; (e) A. Teichert, K. Jantos, K. Harms and A. Studer, Org. Lett., 2004, 6, 3477; ( f ) L.-L. Wu, L. Falivene, E. Drinkel, S. Grant, A. Linden, L. Cavallo and R. Dorta, Angew. Chem., Int. Ed., 2012, 51, 2870; ( g) L. Yin, M. Kanai and M. Shibasaki, Angew. Chem., Int. Ed., 2011, 50, 7620; (h) E. J. Hennessy and S. L. Buchwald, J. Am. Chem. Soc., ¨ndig, Angew. Chem., Int. Ed., 2003, 125, 12084; (i) Y.-K. Jia and E. P. Ku 2009, 48, 1636; ( j) A. Perry and J. K. Taylor, Chem. Commun., 2009, 3249. (a) Y. Liu, B. Jiang, W. Zhang and Z. Xu, J. Org. Chem., 2013, 78, 966; (b) A. Ledwith, P. J. Russell and L. H. Sutcliffe, J. Chem. Soc., Chem. Commun., 1971, 964; (c) Z. Zhang, S. Fang, Q. Liu and G. Zhang, J. Org. Chem., 2012, 77, 7665. S. Maity, T. Naveen, U. Sharma and D. Maiti, Org. Lett., 2013, 15, 3384.
Chem. Commun., 2013, 49, 11701--11703
11703
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Metal-free carbonitration of alkenes using K2S2O8† Cite this: Chem. Commun., 2013, 49, 11701
Ya-Min Li,a Xiao-Hong Wei,a Xi-An Lia and Shang-Dong Yang*ab
Received 24th September 2013, Accepted 15th October 2013 DOI: 10.1039/c3cc47287f www.rsc.org/chemcomm
A novel metal-free oxidative carbonitration of alkenes by a nitration and C–H functionalization cascade process has been developed. This methodology provides an efficient way to construct valuable nitrocontaining oxindoles.
Nitro compounds are widely used in organic synthesis, the chemical industry, and pharmaceuticals. These important synthetic precursors can be easily transformed into various functional groups such as amines and ketones.1 In general, electrophilic aromatic substitution that involves a nitrating agent has been the predominant synthetic approach for the preparation of nitroarenes.2 Recently, transition-metal-catalyzed synthesis of nitroaromatics from aryl chlorides, triflates, and nonaflates has also been developed.3 For aliphatic nitro compounds, however, nucleophilic substitution reaction of an alkyl halide with the nitrite anion (NO2 )4 is the common method. Moreover, oxidation of amines and oximes also affords corresponding nitro compounds.5 These methods require large amounts of base or a specifically functionalized precursor, which significantly limits their application scope. Although direct addition of nitrogen dioxide to a C–C multiple bond provides the simplest pathway of affording aliphatic nitro compounds, the difficulty in handling NO2 gas and its toxicity dramatically decrease the overall reaction efficiency.1a On the other hand, C–C bond-formation reactions involving nitroalkanes also promise alternative methods, including the Henry reaction,6 conjugate additions,7 alkylation of nitroalkanes with alkyl halides8 and Pd-catalyzed allylation,9 and arylation.10 Unfortunately, few substrates are compatible with nitro compounds, which further restricts availability. Therefore, the development of a more concise and efficient nitrating method for the preparation of aliphatic nitro compounds is highly desirable and presents a considerable challenge to research. Recently, transformations that result in the difunctionalization of alkenes have a
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. China. E-mail: [email protected]; Fax: +86-931-8912859; Tel: +86-931-8912859 b State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Lanzhou 730000, P. R. China † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c3cc47287f
This journal is
c
The Royal Society of Chemistry 2013
Scheme 1
Metal-free carbonitration of alkenes.
become an active topic in organic synthesis.11 In particular, transition-metal-catalyzed carbo–heterodifunctionalization of alkenes that leads to cyclization offers a new pathway for the synthesis of various functional oxindoles.12 We envisioned direct installation of the nitro group into alkenes by carbonitration and conducted the necessary cyclization in order to afford the corresponding nitrocontaining oxindoles. After great efforts, we report transition-metal free carbonitration–difunctionalization of arylacrylamides (Scheme 1). Over the past several years, the development of transition-metalfree processes has become a topic of great interest in chemical synthesis.13 Such protocols are very valuable as attractive alternatives and beneficial complements to transition-metal-catalyzed transformations. In particular, the transition-metal-free C–H functionalization has attracted the most attention and achieved significant progress;14 indeed, this of all methods among the metal free processes that involve difunctionalization of alkenes appears particularly fascinating.15 Current reports mainly focus on the oxidative difunctionalization of alkenes; therefore, examples that involve the oxidative carbo–heterocascade cyclization of alkenes are very rare.16 Using the very cheapest NaNO2 as a nitrogen source and K2S2O8 as the oxidant, we first accomplished metal-free oxidative carbonitration of alkenes towards the nitro-containing oxindoles through a radical process. In an initial study, we chose the N-methyl-N-arylacrylamide 1a as the model substrate and NaNO2 as a nitrating source to evaluate different oxidants in CH3CN at 120 1C. To our delight, the carbonitration of alkenes could occur in the presence of 2.0 equiv. of oxidants such as Na2S2O8, (NH4)2S2O8, K2S2O8, and oxone, while the reactivity of K2S2O8 was better than others to afford the desired Chem. Commun., 2013, 49, 11701--11703
11701
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Table 1
ChemComm
Carbonitration of different alkenesa,b
Scheme 2
a
All reactions were carried out in the presence of 0.4 mmol of 1a–1z, NaNO2 (2.0 equiv.), K2S2O8 (2.0 equiv.) in 2 mL of CH3CN at 120 1C. b Isolated yield.
product 2a in 71% yield (see the ESI†). Besides NaNO2, other nitrites could also be used to give good yields of 2a: AgNO2: 66%; KNO2: 70%. The substrate concentration highly affected this transformation. When the substrate concentration was increased to 0.2 M, the yield of 2a improved to 86%. Different solvents were screened, and among them CH3CN exhibited unmatched efficacy for the transformation. Upon optimization of the reaction conditions, we turned our attention to the scope of substrates. As shown in Table 1, an investigation into different N-protection groups showed that the electron-donating groups such as methyl and benzyl are suitable for this reaction (2a–2b). However, replacement of the methyl substituent with a hydrogen atom failed to produce corresponding products. N-Arylacrylamides bearing electron-donating or electron-withdrawing substituents on aniline moieties could be successfully converted into the desired products in moderateto-good yields (2d–2m). Cyclization of a tetrahydroquinoline derivative furnished tricyclic oxindole 2d with moderate yield. Notably, Cl, Br, and I groups were also well tolerated, thereby facilitating possible additional modifications at halogenated positions (2i–2k). Next, we evaluated various alkene substituent groups. A series of a-substituted olefines bearing different functional groups, such as benzyl (2n), acetoxymethyl (2o), phthalimide (2p), and azidoethyl (2q), still provided the desired products in moderate to good yields. It is worth noting that unactivated alkenes can also undergo carbonitration smoothly, generating corresponding products in moderate yields (2r–2x). Finally, the polycyclic aromatic hydrocarbon such as naphthalene was compatible with this reaction and the desired product 2y was obtained in 71% yield. But pyridineacrylamide produced only a trace amount of the product 2z. 11702
Chem. Commun., 2013, 49, 11701--11703
Some reactions on the nitro unit.
Nitro groups feature facile transformation into various functional groups, a versatility that has broadened their importance in the synthesis of complex molecules.1 On the other hand, 3-substituted oxindoles are ubiquitous heterocycles found in a wide range of natural products, pharmaceuticals, and agrochemicals.17 We demonstrate herein the postsynthetic transformations of nitrocontaining oxindoles (Scheme 2). Compound 2a can be further transformed into 1,3-dimethylindolin-2-one (3a) in moderate yield using the oxone–NaOH system. Moreover, KMnO4-oxidized reaction conditions were employed to obtain 3-hydroxyoxindole 3b in good yield from 2a. Finally, compound 2a was also reduced with ammonium formate and Pd/C to give the primary amine 3c. These representative transformations clearly demonstrate that the presented methodology provides an efficient and atom economical access to various valuable 3-substituted oxindoles. To probe the mechanism of the carbonitration process, substrate [D1]-1a was used to determine the intramolecular isotope effect, and a mixture of substrates 1a and [D5]-1a in a 1 : 1 ratio was used to determine the intermolecular isotope effect (see the ESI†). Two secondary kinetic isotope effects were observed (the intramolecular kH/kD = 0.9, intermolecular kH/kD = 0.8). These findings suggested that this transformation reaction might involve a freeradical process similar to mechanisms proposed in previously reports.12e, f,16 In addition, control experiments support the freeradical mechanism in the presence of radical inhibitors. Addition of 2.0 equivalents of TEMPO or 1,1-diphenylethylene would led the carbonitration process remarkably suppressed. Based on the above experiments and previous mechanistic studies,12d–g,16 we propose a tentative pathway of this transformation described in Scheme 3. Initially, potassium peroxydisulphate may decompose to the sulfate radical anion upon heating.18 Then, NaNO2 reacts with the sulfate radical anion to form a nitrogen dioxide radical, followed by addition to the carbon–carbon double bond of amide 1a, thus affording radical intermediate 2A.19 The resulting alkyl radical 2A participates in an intramolecular radical substitution reaction. Addition of a radical to the aromatic ring led to the generation of intermediate 2B, followed by oxidation of 2B into the corresponding carbocation, which loses H+ to produce the oxindole 2a. In summary, we have developed a novel metal-free oxidative carbonitration of alkenes by a nitration and C–H functionalization cascade process using the K2S2O8 as oxidant. This methodology provides the most efficient way to construct nitro-containing oxindoles, which are important synthetic intermediates. Further applications of this new transformation to other substrates and This journal is
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The Royal Society of Chemistry 2013
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12
Scheme 3
Proposed mechanisms for carbonitration of alkenes.
13
the synthesis of more valuable compounds are underway in our group. We are grateful to the NSFC (No. 21272100), Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT: IRT1138) and Research Fund for the Doctoral Program of Higher Education of China (No. 20100211120014) for financial support. We thank S. F. Reichard, MA, for editing the manuscript.
14
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